Preliminary results from ERAS-007 plus palbociclib (palbo) in patients (pts) with KRAS/NRAS mutant (m) colorectal cancer (CRC) or KRASm pancreatic ductal adenocarcinoma (PDAC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).
Authors: Susanna Varkey Ulahannan, David R. Spigel, Michael Sangmin Lee, Marwan Fakih, Patrick Grierson, Eric Christenson, E. Gabriela Chiorean, Darryl Alan Outlaw, Gazala Khan, Chloe Evelyn Atreya, Aparna Raj Parikh, Farshid Dayyani, Alexander I. Spira, Scott Kopetz, Andrea J. Bullock, Zhengrong Li, Xiaoying Chen, Hina Patel, Saswati Hazra, John H Strickler
Journal: Journal of Clinical Oncology (2023)

3558 Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers including CRC and PDAC, resulting in downstream activation of ERK1/2. ERAS-007 is a novel, orally bioavailable inhibitor of ERK. Palbo is an oral CDK4/6 inhibitor that inhibits cellular proliferation, an essential feature of tumor growth. Both in vitro &amp; in vivo data exploring the combination of ERAS-007 and palbo in a panel of CRC and pancreatic CDX and/or PDX models have shown promising activity to support the potential combinatorial clinical benefit in RASm CRC and PDAC pts. Methods: HERKULES-3 is a Phase 1b/2 study to assess safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, and PK of escalating doses of ERAS-007 twice daily-once a week (BID-QW) (75, 100 mg) in combination with palbo once daily (QD) (75, 100, 125 mg) in pts with KRASm/NRASm CRC or KRASm PDAC. Results: As of 30 November 2022, 30 pts were dosed with the combination of palbo and ERAS-007. Treatment emergent AEs (TEAEs) occurring in ≥20% pts were diarrhea (40%), nausea (40%), anemia (33%), vision blurred (27%), fatigue (23%), and neutrophil count decreased (20%). ERAS-007 treatment related AEs (TRAEs) were reported in 19 pts (63%), with the most frequently reported as diarrhea (40%), nausea (33%), and vision blurred (27%). Grade (Gr) ≥3 TEAEs were reported in 12 pts (40%), including 3 related to ERAS-007 (neutrophil count decreased, diarrhea and dermatitis acneiform). Neutrophil count decreased and anemia were the only Gr 3 events reported in ≥2 pts. No Gr 4 events were reported. Two Gr 5 events unrelated to any drugs (hemorrhage intracranial and malignant pleural effusion) and one Gr 5 event (anemia) related to palbo were reported. Two pts discontinued ERAS-007 due to TEAEs (Gr 5 malignant pleural effusion and Gr 2 neutrophil count decreased). Three pts reported 4 DLTs: 1 pt at 75mg ERAS-007 &amp; 125mg palbo (Gr 3 maculopapular rash &amp; Gr 4 sepsis), 1 pt at 100mg ERAS-007 &amp; 100mg palbo (Gr 3 dermatitis acneiform), and 1 pt at 100mg ERAS-007 &amp; 125mg palbo (Gr 3 thrombocytopenia). Based on preliminary PK, no clinically relevant PK interactions were identified between ERAS-007 and palbo. The evaluation of clinical activity is ongoing. Conclusions: ERAS-007 in combination with palbo in pts with KRASm/NRASm CRC or KRASm PDAC shows expected preliminary safety with reversible and manageable AEs. The highest dose evaluated and cleared by the safety review committee to date is ERAS-007 100 mg BID-QW in combination with the approved monotherapy dose of palbo 125 mg QD. Clinical trial information: NCT05039177 .